This is an R21 proposal to study the biological significance of IgE isoforms. In humans, two forms of secreted IgE have been identified. These molecules differ at the COOH terminus owing to alternative mRNA splicing. The functional significance of this difference is unclear but the two isoforms appear to differ in abundance in particular disease states. In the mouse system some monomeric IgE preparations have the ability to promote the survival of mast cells. IgEs with this property are called "cytokinergic." This property is not understood, but it requires binding to FceR1 and is distinct from conventional mast cell activation, which requires crosslinking, rather than simple occupancy of FceR1. It is not clear why certain IgEs are cytokinergic while others are not. Obviously, regulation of mast cell survival could have a major impact on chronic allergic conditions. Mouse IgE H-chain mRNA isoforms homologous to those of human have been described, but no protein information has been available. I hypothesize that these two forms, IgE-S1 and IgE-S2, differ in their bioactivities and hence potential pathogenesis. The prediction will be tested that IgE-S2, but not the normally dominant IgE-S1 form, is cytokinergic. Moreover, we will test if the two IgE isoforms differ in their binding to a newly discovered IgE receptor, Fc?R4. It is important to understand the functions of secreted IgE isoforms and to determine if they differentially control allergic reactions. These goals will be approached through the following Specific Aims. 1. To develop recombinant IgE-S1 and -S2 molecules with identical specificities. 2. To produce series of hybridoma cells producing highly cytokinergic IgE. 3. To compare the bioactivities of IgE-S1 and IgE-S2 by in vivo overexpression. PROJECT NARRATIVE: This is an R21 proposal to study the biological significance of IgE isoforms in allergic disorders. IgE plays a key role in allergic disorders, including asthma and atopic dermatitis. We focus on a specific IgE isoform that may particularly exacerbate allergic symptoms. The goal of the project is to define the role of alternative IgE isoforms in vivo and to determine the IgE isoform contribution against the novel Fc receptor, Fc?R4.